A wide variety of automated analyzers are available, performing analyses that range from simple pH determination to sophisticated testing that determines the presence of genetic markers. Despite this range of functions and capabilities, however, nearly all automated analyzers have common basic functionalities and performance issues. An automated analyzer must manipulate patient samples, which are generally liquids, such as blood, plasma, serum, urine, cerebrospinal fluid, or saliva. Solid or semisolid samples, such as tissue samples and fecal material, can treated as a liquid following maceration and suspension in a liquid. As such samples are provided in containers, such as venous blood collection tubes, and are generally manipulated by aspiration from these containers using one or more liquid handling probes. In order to move these fluids and liquid reagents to different locations on an automated analyzer a liquid handling probe may be attached to a moving carriage.
Automated analyzers generally share a common workflow, each step of which is a potential source of error that can degrade system performance. In a typical automated analyzer containers holding liquid samples are first loaded into the system by the operator. A robotic liquid handling probe then removes a portion of the sample which is used for testing. One or more reagents, which are also generally in liquid form, are retrieved from storage using a robotic liquid handling probe and subsequently mixed with the sample in order to perform an assay reaction that generates a detectable result.
As noted above liquid transfer is a process that is performed frequently on automated analyzers, and is a potential source of error that may degrade the quality of assay results. One assay characteristic that can be severely impacted by such errors is sensitivity, which is essentially a measure of the lowest concentration of a particular analyte that the analyzer can reliably detect or quantify. In many instances the sensitivity of a particular assay is a function of variation in the signal associated with a result from an assay performed on sample that does not contain the analyte, also known as the background signal. A large amount of variation in the background signal results will limit the sensitivity of the analyzer to concentrations of the analyte that return a relatively strong signal, one that is statistically distinguishable from the widely varying background signal. Conversely, a small amount of variation in the background signal can permit the detection of relatively low concentrations or analyte that generate a relatively weak signal.
One source of variation in the background signal is carryover or contamination. Carryover occurs when material is transferred from a first fluid to an analyzer component and then from that analyzer component to a second fluid. A typical scenario is when a small volume of fluid from a patient sample containing a very high concentration of analyte is transferred to a second patient sample by a liquid handling probe, leading to a falsely positive test result from the second sample. Similar transfers of liquid assay reagents are also possible.
Carryover can occur by physical transfer of a volume of fluid. This can occur in crevices that are inherent in the design of the liquid handling probe, or may take place in irregularities in the surface of the liquid handling probe that may occur due to rough handling or inadvertent collisions during use. Another source of carryover is the interaction of specific molecules in the sample with a wetted surface of the liquid handling probe. Once bound to such a surface these molecules may subsequently be released when the liquid handling probe enters a different fluid. Carryover may also occur by a combination of these mechanisms.
A number of approaches have been developed to minimize carryover. One of these is the use of disposable tips to handle fluids. These tips are applied to the liquid handling probe mechanism prior to handling a fluid and disposed of thereafter. Supplying and manipulating these disposable tips can add significant cost and complexity to an automated analyzer, and the time required to attach and dispose of the tips can impact system throughput. Improper attachment of a tip to a liquid handling probe may also lead to delivery of inaccurate volumes that impact assay results, and thereby become yet another source of variation.
Another approach is to implement rigorous washing procedures of the interior and exterior of the liquid handling probe mechanism. Numerous devices and methods for this have been disclosed, however these add significantly to the cost and complexity of an analyzer in the form of the need for additional workstations and wash reagents. In addition to impacting system throughput, these washing steps also are an additional source of variation in the analyzer.
Carryover of fluid volumes can be minimized without resorting to these measures by optimizing analyzer functions to reduce exposure of the liquid handling probe mechanism to the sample, for example by using liquid level sensing to detect the surface of the sample liquid and subsequently immerse only a small portion of the liquid handling probe. The liquid handling probe mechanism itself can be designed so as to present a surface without features that can trap liquids. This can be accomplished by electropolishing exposed metal surfaces and utilizing materials, such as stainless steel, that resist scratching. Positioning of the liquid handling probe can also be monitored to avoid collisions that may generate surface scratches and chips.
Carryover due to the binding of molecules to the material of the liquid handling probe can be avoided by selecting materials with a low tendency to interact with molecules in solution. These are typically polymers, such as polypropylene or fluoropolymers. A liquid handling probe may be constructed entirely of these materials, however the relative lack of strength and rigidity can complicate mounting such devices to motion systems and subsequent accurate positioning, particularly in a high throughput analyzer that may be making rapid movements. In addition, since such materials are generally nonconductive they are not compatible with many liquid level sensing mechanisms. Low nonspecific binding materials can be used as coatings over more conventional rigid materials, such as stainless steel. Such coatings are easily damaged through careless handling and accidental collision, however, generating surface scratches and chips in the polymer coating that can lead to significant fluid volume carryover.
Embodiments of the invention address these and other problems, individually and collectively.